Corticoids with a 16.alpha.-methyl group are known to be useful anti-inflammatory agents. These include dexamethasone (9.alpha.-fluoro-11.beta.,17.alpha.,21-trihydroxy-16.alpha.-methylpregna-1 ,4-diene-3,20-dione), flumethasone 60.alpha.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-16.alpha.-met hylpregna-1,4-diene-3,20-dione) and paramethasone (6.alpha.-fluoro-11.beta.,17.alpha.,21-trihydroxy-16.alpha.-methylpregna-1 ,4-diene-3,20-dione).
The 16-unsaturated corticoid (I) starting materials are known, see, U.S. Pat. Nos. 2,864,834, 3,210,341, 3,839,369, 4,031,080 and 4,277,409.
The transformation of 16-unsaturated pregnanes to 16.alpha.-methyl pregnanes by use of a Grignard reagent is known. The conjugate addition of a 16.alpha.-methyl group to a 16-unsaturated-20-keto steroid by means of a methyl Grignard reagent in the presence of a copper salt catalyst is well known. see Organic Reactions in Steroid Chemistry, Vol II, J. Fried and J. A. Edwards, Van Nostrand Reinhold Co., NY, 1972, p 75. The product of such a reaction is the 16.alpha.-methyl-.DELTA..sup.17 (20) -20-enolate, which according to Fried may be trapped as the 20-acetate, see p 76. While the addition can go 1,2 or 1,4 with a ratio of about 1:1, the addition of cuprous chloride gave exclusively 1,4-addition in yields of greater than 90%.
U.S. Pat. No. 3,231,568 (JULIAN) discloses the transformation of a 16-unsaturated progesterone to the corresponding 17.alpha.-hydroxy-16.alpha.-methylprogesterone. However, JULIAN's pregnane did not have a second .alpha./.beta.-unsaturated ketone in the form of a .DELTA..sup.4 -3-ketone or .DELTA..sup.1,4 -3-ketone as the steroid A-ring was 3,5-cyclo. In addition. JULIAN disclosed a progesterone having no C.sub.21 functionality while the process of the present invention uses a 21-acylate which is sensitive to the Grignard reaction and is hydrolyzable. The C-ring of JULIAN contained no substitution and therefore was not sensitive to the oxidation reaction conditions. A further distinction is that JULIAN traps with acetate and the enol acetate of JULIAN is not reactive to the mild peracid conditions of the present process and hence would not form the desired 17,20-epoxide (III).
U.S. Pat. No 4,031,080 (PALLADINO) uses copper for the conjugate addition reaction but produces an enol acetate which as JULIAN would teach would be unreactive to the mild and selective peracid reaction conditions of this invention producing the desired 17,20-epoxide (III). PALLADINO produces 17.alpha.-bromo-16.alpha.-methyl corticoid not a 17.alpha.-hydroxy-16.alpha.-methyl corticoid.
U.S. Pat. No. 4,277,409 (WARNANT) transforms a 16-unsaturated-21-acetate to a 16.alpha.-methyl-21-acetate, without introducing the necessary 17.alpha.-hydroxyl group while the process of the present invention introduces the desired 17.alpha.-hydroxyl group.
Great Britain Patent 2,001,990 discloses a process to transform a 16-unsaturated corticoid (I) to the corresponding 16.alpha.-methyl corticoid (V) by methylating the 16-unsaturated corticoid with copper catalyzed methyl grignard to produce the 16.alpha.-methyl-.DELTA..sup.17(20) -20-(magnesium bromide)enolate, followed by conversion by oxygenation to a 17.alpha.-hydro-peroxide which is reduced to the corresponding 16.alpha.-methyl-17.alpha.-21-dihydroxy-20-one 21-acetate. The process of the present invention does not produce a 17.alpha.-hydroperoxide, but rather utilizes a 17.alpha.-20-epoxide (III) intermediate.
U.S. Pat. No. 3,072,686 (WETTSTEIN) discloses the transformation of a 16-unsaturated progesterone to a 17.alpha.-hydroxy-16.alpha.-methylprogesterone by reacting the 16-unsaturated progesterone with a Grignard reagent and cuprous chloride. WETTSTEIN produces a .DELTA..sup.17(20) -20-enol acetate which is not reactive to the mild and selective peracid conditions of the present process and hence would not form the desired 17,20-epoxide (III).
Both J. Am. Chem. Soc. 80, 3160 (1958) and J. Am. Chem. Soc. 80, 4428 (1958) report the transformation of a 16-unsaturated progesterone to a 16.alpha.-methylprogesterone by use of a Grignard reagent followed by peracid oxidation to introduce the 17.alpha.-hydroxy group producing a 17.alpha.-hydroxy-16.alpha.-methylprogesterone. The 17.alpha.-hydroxy-16.alpha.-methylprogesterone is brominated and acylated to form the 21-acetoxy-17.alpha.-hydroxy-16.alpha.-methyl steroid.
E. J. Corey in Tetrahedron Letters 26, 6019 (1985), [COREY], discloses the reaction of a methylating agent (lithium dimethylcuperate) with an .alpha.,.beta.-enone in the presence of a trapping agent (chlorotrimethylsilane). The significant difference between COREY and the present patent application is that COREY used preformed alkyl-cuperate where as the present invention generates the cuperate methylating agent in situ. Likewise, A. Alexakis in Tetrahedron Letters 27, 1047 (1986), [ALEXAKIS], discloses the reaction of lithium alkyl-cuperate with unsaturated esters in the presence of trimethylsilyl chloride and demonstrates an increased yield of the alkylated product. However, again ALEXAKIS like COREY used preformed cuperate whereas the present invention generates the cuperate methylating agent in situ.
U.S. Pat. No. 3,700,660 discloses a process of converting a 20-acyloxy-17,20-epoxy steroid to a 17.alpha.-acyloxy-20-keto steroid by use of a strong acid. U.S. Pat. No. 3,700,660 (HEMPEL) uses 20-acetate where the process of the present invention uses 20-silyl. The significance of this is that the .DELTA..sup.17(20) -20-enol silane (II) of the present invention is much more reactive than the corresponding 20-acylate of HEMPEL which permits epoxidation of the .DELTA..sup.17(20) double bond in steroids having other double bonds such as .DELTA..sup.4 -3-keto, .DELTA..sup.1,4 -3-keto, .DELTA..sup.9(11) -etc. whereas the 20-acylate of HEMPEL is limited to a non-functionalized steroid.
U.S. Pat. Nos. 3,513,163 and 4,036,831 disclose C.sub.21 and C.sub.11 trimethyl-siloxy ethers respectively. .DELTA..sup.17(20) -20-O-substituted steroids are known where the substituent is an acyl group or a Grignard substituent (--Mg-X), see U.S. Pat. Nos. 3,072,686, 3,231,568 and 4,031,080. This Mg-X substituted compound while disclosed is not isolatable.
17.alpha.,20-Epoxy-16.alpha.-methyl-20-O-substituted steroids are disclosed in U.S. Pat. No. 3,876,633 where the 20-O-substituent is an acyl group, see claim 9.
Selective epoxidation of the .DELTA..sup.9(11) double bond over the .DELTA..sup.16 double bond in a .DELTA..sup.9(11),16 -diene is set forth in U.S. Pat. No. 3,876,633. U.S. Pat. No. 3,876,633 discloses 9.beta.,11.beta.-epoxy-.DELTA..sup.16 -steroids where the A-ring is reduced. 9.beta.,11.beta.-epoxy-6.alpha.-fluoro-21-hydroxypregna-1,4,16-triene-3,20 -dione 21-acetate is disclosed in U.S. Pat. No. 3,210,341, Example 9(b).
U.S. Pat. No. 4,036,831 discloses a process of protecting the 11.beta.-hydroxyl group of a steroid, during subsequent reactions, with trimethylsilyl and the subsequent removal of the trimethvlsilyl group by hydrolysis with 40-60% aqueous hydrogen fluoride.